The .beta.-lactam ring, ##STR5## has been known since the late nineteenth century. While knowledge of .beta.-lactam chemistry developed during the early 1900's, it was not until 1929 that Fleming reported in Brit. J. Exper. Pathol., 10, 226 (1929) that a fermentation product of the organism Penicillium notatum had antibiotic properties. The compound which Fleming had worked with was benzylpenicillin, ##STR6## The in vivo activity of benzylpenicillin against various bacteria was reported by Chain et al. in Lancet, 2:226 (1940).
During the early 1940's research in the field of penicillins was intense. This research focused first on structure elucidation and then on synthetic routes for preparing benzyl penicillin. It was not, however, until the late 1950's that a totally synthetic route was discovered for the preparation of benzyl penicillin.
U.S. Pat. No. 2,941,955, issued June 21, 1960, to Doyle et al., discloses the discovery of 6-aminopenicillanic acid, ##STR7## This patent was followed by U.S. Pat. No. 2,951,839, issued Sept. 6, 1960, also to Doyle et al., which discloses the use of 6-aminopenicillanic acid as a valuable intermediate which could be acylated, using art-recognized procedures, to obtain penicillin derivatives having antibiotic properties. Using 6-aminopenicillanic as a stepping stone, research chemists have prepared numerous penicillin derivatives having antibiotic activity.
The second major class of .beta.-lactam antibiotics is the cephalosporins. In the 1940's a Cephalosporium species was found to produce an antibiotic that had activity against gram-positive and gram-negative bacteria. Work in the 1950's showed that the fermentation product of a Cephalosporium species contained not one, but several antibiotics. One of these antibiotics, cephalosporin C, ##STR8## proved to be an important stepping stone in cephalosporin research. Removal of the acyl group in the 7-position of cephalosporin C yields 7-aminocephalosporanic acid. ##STR9## an intermediate useful for the preparation of numerous acylated compounds which are analogs of cephalosporin C.
The penicillins and cephalosporins are, of course, the most important of the .beta.-lactam antibiotics reported to date. Others have, however, been reported. Stapley et al., Antimicrobial Agents and Chemotherapy, 2(3):122 (1972) disclose that certain actinomycete cultures isolated from soil produce antibiotics characterized by a methoxy group and a D-.alpha.-aminoadipic acid on the 7-carbon of the cephem nucleus. The cephamycins, as they are known, have the formula ##STR10## cephamycin A: X= ##STR11## cephamycin B: X= ##STR12## cephamycin C: X=--NH.sub.2 Stapley et al. reported that cephamycin A and cephamycin B each exhibits a similar range of potencies against gram-negative and gram-positive bacteria, and cephamycin C had greater potency against gram-negative bacteria than against gram-positive bacteria. Cephamycin C was reported to be the most active of the three antibiotics.
Scannell et al., The Journal of Antibiotics, XXVIII(1):1 (1975), disclose the isolation from a fermentation broth of Streptomyces species 372A of (S)-alanyl-3-[.alpha.-(S)-chloro-3-(S)-hydroxy-2-oxo-3-azetidinyl-methyl]- (S)-alanine, which has the formula ##STR13##
The structure of the above naturally occurring monocyclic .beta.-lactam containing molecule is similar to the structure of the earlier discovered .beta.-lactam containing molecules known as tabotoxins, i.e., ##STR14## wherein X is hydrogen or methyl as reported by Stewart, Nature, 229:174 (1971), and Taylor et al., Biochem. Biophys. Acta., 286:107 (1972).
Recently, several novel series of naturally occurring .beta.-lactam antibiotics have been isolated. The nocardicins, nocardicin A and B, are monocyclic .beta.-lactams having the formula ##STR15## nocardicin A: Y.dbd.--syn(Z)OH nocardicin B: Y----anti(E)OH,
as reported by Hashimoto et al., The Journal of Antibiotics, XXIX (9):890 (1976).
Clavulanic acid, a bicyclic .beta.-lactam antibiotic isolated from fermentation broths of Streptomyces clavuligerus, has the formula ##STR16## i.e., Z-(2R,5R)-3-(.beta.-hydroxyethylidene)-7-oxo-4-oxa-1-azabicyclo[3,2,0]hept ane-2-carboxylic acid, as reported by Lloyd et al., J.C.S. Chem. Comm., 266 (1976).
Still another recently isolated .beta.-lactam antibiotic is thienamycin, an antibiotic isolated from the fermentation broths of Streptomyces cattleya. As reported by Albers-Schonberg et al., J.A.C.S., 100:20, 6491 (1978), thienamycin has the structure ##STR17##
Additional fused .beta.-lactams, olivanic acid derivatives, have recently been isolated from cultures of Streptomyces olivaceus. As disclosed by Brown et al., J.C.S. Chem.Comm., these olivanic acid derivatives have the formulas ##STR18## The isolation of the above antibiotics, and a discussion of their activity, is reported by Butterworth et al., The Journal of Antibiotics, XXXII(4):294 (1979) and by Hood et al., The Journal of Antibiotics, XXXII(4):295 (1979).
Another recently isolated .beta.-lactam antibiotic is PS-5, reported by Okamura et al, The Journal of Antibiotics, XXXI: 480 (1978) and The Journal of Antibiotics, XXXII(4):262 (1979). The structure of this antibiotic, which is produced by Streptomyces cremeus subspecies auratilis, is reported to be ##STR19## Structurally related antibiotics PS-6 and PS-7 are reported in European Patent application serial number 1,567 to have the respective structures ##STR20##
Two recently disclosed series of .beta.-lactam antibiotics are the monocyclic .beta.-lactams having the formulas ##STR21## wherein R.sub.e is hydrogen or alkoxy, R.sub.c and R.sub.d are various organic substituents and M.sup..sym. is a cation. The antibiotics having an --SO.sub.3.sup..crclbar. M.sup..sym. activating group are disclosed in United Kingdom patent application No. 2,071,650, published Sept. 23, 1981. The antibiotics having an --O--SO.sub.3.sup..crclbar. M.sup..sym. activating group are disclosed in U.S. Pat. No. 4,337,197, issued June 29, 1982.